Glycoproteins, particularly monoclonal antibodies of rat or mouse origin, are increasingly being used for the treatment and diagnosis of cancer, infections, and immunological diseases. When administered to the patient, an immune response is sometimes generated by patients against these antibodies. The response is defined by the difference between the reactivity of the pre- and that of the post-treatment serum or plasma with the infused antibody.
Regulatory agencies require the monitoring and quantification of human immune response to the administered glycoprotein in treated patients. However, pre-dose reactivity of human serum or plasma, in some cases, is high and may interfere with the monitoring and quantification of the specific immune response to the glycoprotein.
In most situations, and although most of the patients are naive with respect to exposure to these proteins, a pre-treatment serum reactivity with the therapeutic protein is typically detected. This reactivity can be attributed to the presence in human serum or plasma of "natural antibodies" reactive with the antibody and in particular with the carbohydrate portion of the administered glycoprotein. Since the pretreatment serum reactivity with the glycoprotein might either conceal or augment the real immune response, reduction of this reactivity is desired.
Awwad M, Strome PG, Gilman SC, and Axelrod HR, Modification of monoclonal antibody carbohydrates by oxidation, conjugation, or deoxymannojirimycin does not interfere with antibody effector function, Cancer Immunology Immunotherapy, 38:23-30 (1994) examined site-specific modification of monoclonal antibody (mAB) by periodate oxidation and subsequent conjugation to either a peptide linker/chelator or a cytotoxic drug. These mAB-associated carbohydrates were also modified metabolically by incubating hybridoma cells in the presence of a glucosidase inhibitor (deoxymannojirimycin) to produce high-mannose antibody. It was concluded that modification of mAB carbohydrates did not compromise their in vivo or in vitro biological functions and that, therefore, combination therapy using immunomodulators to enhance the effector functions of site-specific immunoconjugates could be seriously contemplated.